Sex differences in reward network activation are linked to problematic substance use among high-risk adolescents

Abstract

Background: Adolescents with externalizing (EXT) disorders, such as attention-deficit/hyperactivity disorder and conduct disorder—characterized by impulsivity and rule-breaking, are at elevated risk for substance use disorders (SUDs), partly due to deficits in risky decision-making. Sex differences in this association are understudied. Neuroimaging research shows females and males with EXT disorders exhibit different brain activation patterns during risky decisions. This study will explore how these sex differences relate to the development of problematic substance use in youth with EXT disorders.Method: A total of 115 (78 males, 37 females) drug-naive adolescents with EXT psychopathology performed the Balloon Analogue Risk Task (BART) during magnetic resonance imaging to assess risky decision-making brain activation. Then, participants and their guardians completed questionnaires at six-month intervals to assess problematic substance use. Statistical analyses evaluated sex differences in brain activation—both parametrically modulated and unmodulated—within a priori-selected regions associated with risky decision-making and problematic substance use, using Cox proportional hazards models.Results: Higher modulated brain activation (as explosion probability increased) during the choice phase contrast, Choose Inflate—Choose Win, was associated with a lower hazard of problematic substance use in the right nucleus accumbens (Hazard Ratio (HR) = 0.68, 95% CI [0.49, 0.94], p = 0.01). This association was significant for females, but not for males, with the hazard ratios being significantly different between sexes. In the right nucleus accumbens, higher unmodulated choice phase activation in males was associated with lower hazard of problematic substance use (HR = 0.60, 95% CI [0.37, 0.97], p = 0.03); and in the right subgenual anterior cingulate cortex, higher unmodulated activation in this same contrast in females was associated with a lower hazard of problematic substance use (HR = 0.49, 95% CI [0.24, 0.97], p = 0.03).Conclusions: This study offers insight into sex differences in risky decision-making neural mechanisms and SUD risk among youth with EXT disorders. Our findings suggest typical risk signaling in the reward-processing network (nucleus accumbens and subgenual anterior cingulate cortex) may protect against substance use, particularly in females with EXT disorders. These findings emphasize the need for further sex-specific research and interventions for youth with EXT disorders.